Genotype and Phenotype in Familial Dysautonomia

Publisher Summary Clinical features of familial dysautonomia (FD) encompass sensory and autonomic disturbances. Consistent peripheral neuropathologic findings suggest arrested development of the unmyelinated neuronal population, as well as progressive neurological deterioration. Plasma levels of catechols, as well as their metabolites have been investigated to define better the neurochemical phenotype and elucidate possible pathophysiological mechanisms. It has been demonstrated that FD patients have disproportionately high plasma levels of dihydroxyphenylalanine (DOPA) and low plasma levels of dihydroxyphenylglycol (DHPG), with strikingly elevated plasma DOPA/DHPG ratios. This pattern of plasma catechols is distinctly different than that found in other disorders associated with neurogenic orthostatic hypotension. Patients with acquired dysautonomia because of multiple system atrophy have normal supine norepinephrine (NE) and normal DOPA/DHPG ratios. Patients with dopamine β -hydroxylase (DBH) deficiency had barely detectable levels of NE when supine, no detectable DHPG, markedly elevated DOPA and dihydroxyphenylacetic acid (DOPAC) levels, and extremely high DOPA/DHPG and DOPAC/DHPG ratios. The normal supine NE levels but low DHPG levels in FD are intriguing. The normal supine plasma NE levels in FD patients are also consistent with decreased neuronal re-uptake of released NE because of sparse sympathetic innervation and perhaps ongoing constitutive neurosecretion. These studies may guide genetic investigators toward factors that would influence neurodevelopment, as well as differentiation of catecholaminergic systems.